RA is a type of inflammatory arthritis. Other examples include seronegative spondyarthritides, reactive arthritis, lyme arthritis, crystal arthritis and postviral arthritis.
Features of inflammatory arthritis
- Pain and stiffness worse in the morning and after rest
o Early morning pain and stiffness may last several hours (in OA, duration is much shorter)
- Inflammatory markers (ESR, CRP) usually raised
This is a chronic symmetrical arthritis. When we say it is symmetrical, we don’t necessarily mean a mirror image, just that the same joints are affected on both sides of the body. it is also important to remember that RA is a systemic condition, with many extra-articular manifestations.
Typically it affects the peripheral joints, and there is inflammation of the joint (synovitis). Deformity is common and the course is extremely variable.
Epidemiology and Aetiology
- affects 0.5-3% of the population worldwide
- can present at any age (from childhood to old age), but the peak incidence is between 30-50 years
- women affected more than men (M:F – 1:2)
o before the menopause, risk is 3x higher for women
o after the menopause it is equal
§ suggests sex hormones involved in some way
§ the contraceptive pill can delay the onset, but does not reduce the risk
- Genetic factors are involved. Certain HLA variants are implicated, especially in severe forms of the disease:
o HLA-DR4 – occurs in 50-75% of patients, and is associated with a particularly poor prognosis
o HLA-DR1 is another variant associated with RA, and poor prognosis
- Environmental factors:
Most commonly, the condition will present as progressive over weeks to months. These patients have the worse prognosis. But in some cases it can come on in days, or even overnight. Also, it is almost always a polyarthritis, but some cases do present as monoarthritis, most commonly of the knee or shoulder, or with carpal tunnel syndrome.
- symmetrical swollen distal joints
o Often warm and tender joints
o sometimes presents as a sudden onset of widespread arthritis, but this is rare.
o Typically the joint of the hand (MCP, DIP and PIP’s)and the distal metatarsals of the foot.
§ Sometimes it affects the wrists, elbows, shoulders, knees and ankles.
§ Hips are very rarely affected
o Limitation of movement
o Muscle wasting
- Pain and stiffness – worse in the morning, may improve with activity. It is often described as an ache type pain.
- Disturbed sleep
- Nodules – in the early and mild stages of the disease, there are relatively few inflammatory cells in the joints. As the disease progresses, these increase in number and there may be nodular masses of inflammatory cells within the joint. Rheumatoid nodules occur when these inflammatory cells form similar inflammatory structures outside of the joint capsules. The nodules are usually pink/red and have a rubbery texture. They are painless. You should always check the elbows in a hand exam, looking for rheumatoid nodules!
- Osteoporosis – often occurs in the bones immediately around the affected joints, particularly in the fingers. This may be the first sign of RA.
- Secondary Osteoarthritis
- Deformity – as the joint capsule is destroyed, and the articular surface damaged, deformity occurs. Specific examples include
§ Swan necking – the fingers become hyperextended at the PIP, and flexed at the DIP
§ Subluxation of the MCP –not that this is not swelling!
§ Muscle wasting – “guttering” – ‘gutters’ seen between the extensor tendons on the back of the hand.
· Why do the muscles waste so quickly in joint disease? – in a normal individual, if you don’t use a muscle, it will waste at a rate of about 1% of its mass/day. However, in joint disease, the rate of wasting in much greater. This is because in joint disease, there is inhibition of nerve afferents, for nerves that innervate the muscles around a joint. This alters the muscle tone/reflex feedback loop, leading to decreased innervation of the muscle, and as a result, wasting occurs very quickly.
§ Inflamed flexor tendon sheaths – these serious impair function.
§ Carpal tunnel syndrome is common
§ Ulnar deviation – the fingers point towards the ulnar side
§ Fixed flexion deformity – aka buttonhole or boutonniere deformity
o Shoulders - Shoulders are commonly affected, and at first it may mimic rotator cuff tendonitis. Later, the joint becomes stiffened. Rotator cuff tears can occur late on.
o Elbows – less commonly affected. Flexion may be lost, which makes eating very difficult
o Knees – massive synovitis and effusion. These respond well to steroid injection and aspiration. A persistent effusion may increase the risk of cyst formation, and these can rupture. Varus or valgus deformity can occur, and there may be joint space narrowing and secondary OA.
§ Knee replacement can restore much of the function, and relieve pain.
o Cervical spine – pain in the neck is more commonly muscular, but you can get joint disease itself in the cervical spine. There can be bone destruction, which poses a risk to the spinal cord.
§ Be wary loss of sphincter control, or unexplained weakness in late RA – could be due to cord compression!
o Feet – often the first signs of the disease may only be in the feet. The patient may describe an uncomfortable sensation that feels like walking on marbles. This is due to subluxation of the heads of the metatarsals in the feet.
The symptoms of RA are often worse in the summer / hot weather – eg. If the patient goes on holiday.
- Subcutaneous rheumatoid nodules
o Occur in about 1/3 of patients, usually in severe progressive cases. They most commonly occur on the extensor surfaces of the forearm, and sometimes on the dorsum of the foot. Sometimes also on the Achilles tendon.
o They have a central area of necrotic collagen, surrounded by marcophages and fibroblasts. This resembles the synovitis – but there is no synovium!
o Usually 2-4cm in diameter
o Occur over pressure points
o Can be removed surgically, or injected with corticosteroids, and they will reduce over time if they are problematic, however, they will usually recur.
- Swollen bursae – particularly the olecranon.
- Anaemia – almost always occurs, and is usually normocytic, normochromic. Can sometimes be iron-deficiency related, due to NSAID’s.
- Lymphadenopathy - nd can
- Sjogren’s syndrome
o Salivary glands and tear ducts are destroyed, resulting in dry eyes and dry mouth
- Vasculitis – a very poor prognostic sign. Usually occurs in the fingers. It is the result of immune complex deposition in arterial walls. Smoking greatly increases the risk. Signs to look out for include:
o Nail fold infarcts
o Necrosis of the skin
o Bowel infarction – due to arterial involvement in the bowels
- Septic arthritis – serious! – has a high mortality and morbidity. May present as a sudden onset effusion. Any sudden onset effusion needs to be aspirated! Staph. A. is the most common causatory organism. Treat with systemic AB’s and drainage.
- Heart signs:
o Pericarditis – rare, but in 30% of seropositive patients, there is some pericardial involvement
o Endocarditis – even rarer
- Reynaud’s phenomenon
- Peripheral neuropathies – often in glove and stocking pattern. May also get mononeuritis multiplex (many nerves involved, but not in a distinct pattern). Usually sensory.
- Kidneys – nephrotic syndrome and renal failure
- Ruptured tendons
- Ruptured Baker’s cysts
- Depression – commonly occurs in RA patients
Eye Changes in Rheumatoid arthritis
The best way to remember them is to go from the outside, in.
- Dry eyes – can be managed with artificial tears.Also common in Sjogren’s syndrome – an autoimmune disorder associated with RA
- Episcleritis – inflammation of the covering of the sclera. Often causes mild discomfort and redness of the eye. Managed with steroid eye drops and anti-inflammatories. The blood vessels can look particularly prominent.
- Scleritis – inflammation of the sclera (White part of the eye). Causes constant severe eye pain. More serious than episcleritis, and often requires referral to ophthalmology. May be managed with steroid eye drops and anti-inflammatories.
o in scleritis and episcleritis, the sclera can become thin. It may appear blue due to thinning, and sometimes the contents of the eye ball can bulge out,
- Cataracts – can be caused by inflammatory processes within the eye, but also can be caused by the steroid eye drops used to treat this inflammation. Usually causes cloudy, blurred and/or dim vision. The only effective treatment is surgery for lens replacement.
- Uveitis – inflammation of the interior of the eye. Acute visual loss and pain. May affect the iris, where the boarder of the iris becomes jagged. Treatment is with steroid eye-drops and anti-inflammatories
- Glaucoma – in the case of RA, usually caused by inflammatory processes within the eye. Very dangerous, as it can lead to visual loss. May present with eye pain, gradual visual loss, blurred vision. Can be treated with eye drops, but may require surgery.
- Hydrochlorequine – can cause ‘floaters’ and retinopathy. This is usually reversible and will disappear when the drug is stopped
- Steroids – can cause an eye muscle myopathy – eye movements may be reduced. They can also impair the immune system, making patients more prone to conjunctivitis.
Pulmonary changes in RA:
- Diffuse pulmonary fibrosis – will shows as a restrictive pattern on spirometry. SOB in RA patients can be particularly serious. Often RA patients have very poor mobility, and so when they get SOB,you know it must be sever, because they are hardly doing anything to increase the O2 requirements!
o How to remember the causes of lung fiobrosis:
§ All connective tissue diseases cause lower lobe fibrosis – except AS, which causes upper lobe fibrosis
§ All occupational diseases cause upper lobe fibrosis, except asbestosis, which causes lower lobe fibrosis
§ Remember, the ‘A’ are the exception!
- Lung nodules – these are specific to RA, and are basically the same as the subcutaneous nodules, but they form in the lungs. They are generally asymptomatic, but they can cavitate.
- Pleural effusion – often recurrent
- Palindromic – monoarticular attacks, last 24-48 hours. 50% of cases will progress to other types of RA
- Transient – lasts <12 months, then permanently remits. Usually seronegative. No lasting damage
- Remitting – may be active for several years at a time, before remitting. Lasting damage is minimal
- Chronic, persistent – the most common form. May be seronegative or seropositive. Follows a relapsing remitting course over many years. Seropositive patients have worse joint disease and higher risk of long-term disability.
- Rapidly progressive – rapid progression occurs over several years. Severe joint damage, disability and high rate of complications
RA is a kind of autoimmune disease. We say that the patient is in a hyperimmune state. There is thought to be some T cell activity, but factors released by T cells (IL-2 and IL-4 amongst others) are not very abundant. Macrophages products and activity however, are very prominent. This means that rather than RA being a ‘true’ autoimmune disease, involving some dysfunction in the immune system, the dysfunction is on a cellular level.
In most cases, the reaction is mediated by rheumatoid factor. This is an antibody against IgG (which is itself and antibody!). Specifically, RF is an antibody against the Fc portion of the IgG molecule. Rheumatoid factor and IgG will join together to from immune complexes , which activates complement, and sets of the inflammatory process.
- Various rheumatoid factors are produced in normal individuals, and physyiologically, they are used to remove old IgG from the blood. But in RA, something goes wrong
- About 70% of cases of RA have RF’s in the blood
o Patients who have seronegative disease tend to have a baetter prognosis, and disease that is just limited to synovial manifestations
- RF’s are themselves generally IgM, but they can be IgG or IgA.
Cases of RA where rheumatoid factor is not present are referred to as seronegative RA.
Rheumatoid factor is also present in many individuals who do not have RA.
It is thought that like many other ‘autoimmune’ type disease, an infection earlier in life may be implicated.
In terms of joint disease, RA results in:
- Chronic inflammatory synovitis
- Progressive erosion of articular cartilage, which exposes the underlying bone.
- Pannus- this is essentially the inflamed synovium. It damages the cartilage by restricting its normal nutrient flow, and by released inflammatory factors.
- Cytokines cause:
o increased bone turnover rate
The diagnosis can be made clinically. The American college of rheumatology (ACR) criteria are:
- Morning stiffness >1 hour
- > 3 joints involved
- Hands and wrist involvement
- Positive RF
- Radiological changes
- Symptoms present for > 6 weeks
These criteria are only really used for studies, and are not useful in early disease.
Normal initial investigations
- Blood count:
o ESR/CRP raised due to inflammation. Monitoring levels of these can be used to assess treatment
- Serology – check for rheumatoid factor – only present in 70% of cases.
o ANA’s – anti-nuclear antibodies – these are also regularly tested for, and show up in 30% of cases
o Anti-CCP – testing for this is becoming more common.
- X-ray – useful to get a baseline reading at the start of the disease. Normally only soft tissue swellings initially. Later there may be:
o Boney erosions
o Osteopenia (lower than normal bone density)
- Joint aspiration – in the presence of effusion. Aspirate will appear cloudy due to the presence of white cells. If the joint is suddenly painful, always aspirate to check for septic arthritis, as this can rapidly destroy joints.
- MRI – very rarely used, but can show early bone erosions. Also used in widespread disease to assess the extent of the joint damage.
There are loads of differentials, particularly if the symptoms are only transiently present for a few weeks (eg. Viral arthritis). If you get asked in the OSCE, the main differential is SLE!
Increasingly, the aim of treatment is to minimize joint damage.
NSAID’s are widely used for symptomatic relief. They do not alter the disease progression in any way. Other basic analgesics (including paracetomol and codeine) are usually ineffective at controlling pain, but may still be used. You should aim to use a COX-2 specific drug to reduce the risk of GI complications, although in relation to RA, the outcome of selective vs non-selective agents is identical.
- In all patients over 65, and those with previous history of GI problems, you should use gastric protection (e.g. omeprazole).
These are very useful in inducing remission. Some studies have shown that low dose (7.5mg prednisolone) reduced both symptoms, and progression of the disease. However, you need to give something to prevent osteoporosis, and many doctors have concerns about long-term steroid use. However, steroids are used widely in RA.
- The exact dose and length of regimen that is most beneficial is still not widely accepted
- Remember to look for signs of long-term steroid use when examining for rehaumatological and arthritis conditions! – if there are any, then these patients will nearly always be RA.
- Steroids are also used in acute flare ups of the disease (typically an IM preparation 80-120mg).
They are also used acutely and injected into joints that are severely inflamed.
DMARD’s – Disease modifying anti-rheumatic drugs
Functional impairment and pathological joint damage can be reduced when these are used. The earlier in the disease course they are used, the more damage can be prevented.
DMARD therapy should be initiated ASAP after diagnosis.
Nearly all DMARD therapy takes between 6-12 weeks to take effect. They will reduce symptoms (according to ACR criteria) in 20-50% of patients.
All treatments (except hydrochlorequine) require regular blood test monitoring, and should all generally be avoided during pregnancy.
Most DMARD’s act by inhibiting cytokines. This reduces irreversible joint damage.
- Methotrexate –an antifolate drug, often used to treat cancer, but also effective in autoimmune disease. Probably the most widely used drug in RA. It generally targets cells with a high turnover rate (folic acid is needed to synthesize DNA)this is generally the first line treatment and is often given weekly (25mg dose) or daily (3mg).
o Side effects – can cause mouth ulcers, GI upset, (due to the high cell turnover rates in these areas) and possibly liver and haematological disturbances. GI Side effects can be reduced by giving folic acid supplement – folic acid should be taken once per week, and blood test for folate levels taken every two weeks.
§ Liver problems
§ Shouldn’t take with alcohol
o Less effective than anti-TNFs, but also, much cheaper, so NICE recommends try this first, before anti-TNF’s.
- Sulfasalazine – initially used in IBD, also effective in RA. Not quite as well tolerated as methotrexate.
o Mechanism - not really understood. Thought that it inhibits inflammatory mediators, but does not directly cause immunosuppression.
o Side effects –myelosuppression, nausea, rash, oral ulcers, decreased sperm count
- Leflonamide – often used as an alternative to sulfasalazine. Similar side effects. Contra-indicated in pregnancy.
- Hydrochlorequine – this is the least toxic of these agents, but probably also the least effective. Causes rashes and retinopathy – vision should be checked at least every 12 months.
- Gold – given IM. More toxic than sulfasalazine or methotrexate. Causes myelosuppression, renal toxicity, mouth ulcers, and photosensitivity
**DMARDS’s can be combined if they are not producing therapeutic benefit on their own**
- Myelosuppression – (bone marrow suppression) - can be caused by pretty much all of the DMARD’s. leads to a pancytopenia, and can be dangerous is it greatly increase susceptibility to infection. Can cause death if there is severe sepsis.
Anti-TNF-α - e.g. etanercept, infliximab, adalimumab
This is used in patients who fail to respond to DMARD’s. TNF-α is one of the crucial cytokines involved in the inflammatory response. It is effective in up to 70% of patients, and is growing in popularity as a treatment. It relieves symptoms, and reduces disease progression, like other DMARDS’s. it is very expensive! – hence on the NHS, other DMARD’s are tried first. NICE guidelines tate to use these only after 2 other DMARD’s have been unsuccessful.
- Side effects – can allow the reactivation of latent infections, such as TB – as TNF-α is involved in the maintenance of these latencies. However, these agents are actually usually well tolerated compared to other DMARDs.
o Long-term safety is not known. Some concerns about increased cancer risk, but unproven.
- Contra-indications – pregnancy / breast feeding, ongoing infection, heart failure
Exercise and physiotherapy – should always be encouraged.
Managing other risk factors:
- Cardiovascular disease risk is increased – due to atherosclerotic effects of RA
- Smoking –increases the risk of RA. Stopping smoking may be beneficial
As always, the best care is patient centred, and provided by a multidisciplinary team! – if you are asked about treatment in the OSCE, remember to say these two things!
Modern treatments have greatly reduced the degree of deformity, and improved function for many patients. However, it many cases it is still very disabling. Many patients are able to cope remarkably well despite reduced function. Functional aids help (e.g. modified cutlery, kitchen tools, and modifications on taps (for turning) and stairways etc.).
There is also an increased mortality risk (About 1.5x that of the general population), due mainly to cardiovascular involvement of the disease. The risk of mortality is increased most in those with extra-articular manifestations, and in the most aggressive disease types.